WO2004071518A1 - Remede contre le cancer - Google Patents

Remede contre le cancer Download PDF

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Publication number
WO2004071518A1
WO2004071518A1 PCT/JP2003/014252 JP0314252W WO2004071518A1 WO 2004071518 A1 WO2004071518 A1 WO 2004071518A1 JP 0314252 W JP0314252 W JP 0314252W WO 2004071518 A1 WO2004071518 A1 WO 2004071518A1
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WO
WIPO (PCT)
Prior art keywords
cancer
cells
vascular endothelial
cell
dendritic cells
Prior art date
Application number
PCT/JP2003/014252
Other languages
English (en)
Japanese (ja)
Inventor
Naoki Utoguchi
Kazuo Maruyama
Original Assignee
Mebiopharm Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mebiopharm Co., Ltd. filed Critical Mebiopharm Co., Ltd.
Priority to CA002511623A priority Critical patent/CA2511623A1/fr
Priority to MXPA05008687A priority patent/MXPA05008687A/es
Priority to EP03815859A priority patent/EP1595546A4/fr
Priority to JP2004568205A priority patent/JPWO2004071518A1/ja
Priority to US10/544,631 priority patent/US20060062766A1/en
Priority to AU2003277641A priority patent/AU2003277641B2/en
Publication of WO2004071518A1 publication Critical patent/WO2004071518A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/55—Lung

Definitions

  • the present invention relates to cancer immunotherapy targeting vascular endothelial cells of tumor tissue.
  • Therapies for cancer include surgical therapy, chemotherapy, and radiation therapy. Each has its own characteristics, and the most effective cancer treatment is selected in consideration of their characteristics.
  • Surgery is an effective method for cancers of a certain size or larger, but the invasiveness of surgery is extremely burdensome for patients, and it is difficult to remove sites such as brain tumors and several millimeters. The difficulty of finding such small cancers is the limitation of external therapy.
  • Chemotherapy is mainly performed by injection or oral administration, so that the burden on the patient is light.
  • anticancer drugs are transported via blood, it can be applied to small tumors.
  • anticancer drugs are basically cytotoxins, and their side effects are extremely serious, and sufficient effects are often not obtained due to restrictions on the amount and period of use.
  • Radiation therapy has problems in that it is difficult to selectively irradiate the target site with radiation, and it also affects nearby normal cells.
  • cancer immunotherapy that eliminates cancer by "immunity", which is the system of foreign body elimination inherent in the living body.
  • Early cancer immunotherapy adjuvanted cancer cell fragments and cancer-specific antigens
  • the drug is administered as a cancer vaccine together with drugs and the like to activate cytotoxic T cells (CTLs) and eliminate cancer, but cancer cells themselves are originally their own cells that have changed. Poor antigenicity and little success in cancer immunotherapy.
  • CTLs cytotoxic T cells
  • Dendritic cells are cells that have the strongest antigen-presenting ability in vivo. Therefore, in an ex vivo system, cancer cell fragments and cancer-specific antigens are pulsed into dendritic cells, and the dendritic cells are returned to the living body, whereby the dendritic cells activate CTLs and cancer is immunized by cancer immunity. It is to be eliminated. Cancer immunotherapy using dendritic cells has been reported not only in animal experiments but also in clinical results in humans, and its potential and efficacy are attracting attention as a novel cancer treatment (J. Immunol., 156, p. 2918 (1996), J.
  • An object of the present invention near-Q 0 to provide a new cancer immunotherapy using dendritic cell function
  • the present inventor focused on the fact that tumor tissue has a higher growth rate than normal tissue, and it is essential to supply nutrients and angiogenesis as a pipe for eliminating waste products.
  • dendritic cells are useful as cancer immunotherapy drugs targeting vascular endothelial cells in tumor tissues. They found that cells could be obtained, and completed the present invention.
  • the present invention relates to vascular endothelial cells cultured in a medium containing a cancer cell culture supernatant. It is intended to provide a therapeutic agent for cancer comprising, as an active ingredient, dendritic cells stimulated with a derived antigen.
  • the present invention also provides use of dendritic cells stimulated with vascular endothelial cell-derived antigens cultured in a medium containing a cancer cell culture supernatant for the production of a therapeutic agent for cancer.
  • the present invention provides a method for treating cancer, which comprises administering dendritic cells stimulated with an antigen derived from vascular endothelial cells cultured in a medium containing a culture supernatant of cancer cells. is there.
  • the cancer therapeutic agent of the present invention is a cancer immunotherapy targeting vascular endothelial cells of tumor tissue instead of targeting tumor cells themselves. Therefore, they are superior to the conventional cancer immunotherapy in the following points.
  • FIG. 1 shows the therapeutic effect (lung weight) of dendritic cells stimulated with vascular endothelial cell-derived antigens cultured in a medium containing B16 cancer cell culture supernatant on mouse lung cancer.
  • None is B1 6 alone administration group; None pulsed DC is B16 and nothing pulses to have a I dendritic cells administered group; BAEC pulsed DC are dendritic cells administered group pulsed with BAEC; B1 6 CM -BAEC pulsed DC indicates a group to which B16 and dendritic cells pulsed with BAEC cultured in the culture supernatant of B16 were administered.
  • Dendritic cells which are active ingredients of the therapeutic agent for cancer of the present invention, target vascular endothelial cells of tumor tissue. Therefore, vascular endothelial cells for stimulating dendritic cells are those cultured in a medium containing a cancer cell culture supernatant.
  • the cancer cells used are preferably human cancer cells, but the type of cancer cells is not limited.
  • cancer cells include solid cancer cells such as stomach cancer, liver cancer, colorectal cancer, lung cancer, skin cancer, bladder cancer, child cancer, ovarian cancer, breast cancer, prostate cancer, and brain tumor.
  • the conditions for culturing the cancer cells are not particularly limited, for example, in a medium such as RPMI1640, MEM ⁇ DMEM, Ham F12, M199, or the like. C, 5% C0 2, 9 5% air, have preferably carried out saturated steam conditions.
  • the medium can also be supplemented with antibiotics, sodium bicarbonate, non-essential amino acids, and the like.
  • the culture supernatant of the cancer cells can be collected, for example, by centrifugation at 500 to 150 O rpm for 2 to 10 minutes or filtration with a filter.
  • the species of the vascular endothelial cells is not particularly limited, and vascular endothelial cells of humans, mice, mice and the like are used.
  • vascular endothelial cells of blood vessels such as umbilical vein, umbilical artery, aorta, pulmonary artery, neonatal foreskin, and adult skin are used.
  • the vascular endothelial cells are cultured in a medium containing the cancer cell culture supernatant.
  • the amount of the culture supernatant of cancer cells added to the medium is preferably 10 to 10 Ov / v%, particularly preferably 20 to 10 Ov / v%.
  • the medium for vascular endothelial cell culture is not particularly limited.
  • RPMI1640 M A medium such as EM, DMEM, Ham F12, and M199
  • a vascular endothelial cell growth factor, heparisi, an antibiotic, etc. may be added in addition to the cancer cell culture supernatant.
  • the conditions for culturing vascular endothelial cells are not particularly limited, and the vascular endothelial cells are preferably cultured under conditions of 37 ° C., 5% CO 2 , 95% air and saturated steam for 2 to 4 days.
  • the vascular endothelial cell-derived antigen may be the vascular endothelial cell itself, but may also be a vascular endothelial cell component (for example, total RNA), a vascular endothelial cell lysate or a vascular endothelial cell membrane vesicle.
  • a vascular endothelial cell component for example, total RNA
  • a vascular endothelial cell lysate or a vascular endothelial cell membrane vesicle.
  • the intracellular components, cell framing fluid and membrane vesicles are more preferred because they are easy to prepare and have high stimulation efficiency for dendritic cells.
  • the cell lysate can be obtained, for example, by centrifugation (40 ° C, 10 minutes) at a low speed by repeatedly freezing (160 ° C) and thawing (37 ° C) 4 to 6 times.
  • membrane vesicles for example, 1 0 O mM paraformaldehyde in DMEM, 2 mM Jichiosurei torr, 1 niM CaCl 2, 0. 5 niM MgCl 2 to 3 7 ° C in plus, 5% C0 2, 9 Treat overnight under 5% air and saturated steam conditions, then centrifuge at 150 g for 5 minutes, then prepare the supernatant by centrifugation at 300 ° C for 30 minutes at 4 ° C. be able to.
  • Intracellular components for example, Total RM, can be prepared by a conventional method.
  • dendritic cells it is preferable to use human-derived dendritic cells, in particular, dendritic cells from the patient to be administered, or human-compatible dendritic cells with the patient.
  • Dendritic cells can be obtained by inducing differentiation from bone marrow cells, cord blood-derived cells, peripheral blood mononuclear cells, and the like, for example, by the methods described in Non-Patent Documents 8, 9 and the like.
  • dendritic cells from peripheral blood mononuclear cells, for example, in a medium containing GM-CSF (10-lOOng / mL) and IL-4 (50-500IU / mL) for 5 to 10 days
  • GM-CSF 10-lOOng / mL
  • IL-4 50-500IU / mL
  • cytolysis of dendritic cells and vascular endothelial cells may be presented to dendritic cells by law.
  • the total RNA of vascular endothelial cells may be introduced into dendritic cells to present the antigen.
  • the amount of the antigen to be added is preferably from 0.1 to 100 / zg Zm as protein concentration per 1 ⁇ 10 6 dendritic cells, particularly preferably from 0.1 to 100 ⁇ g / mL.
  • the dendritic cells thus obtained present the vascular endothelial cell-specific antigen of the cancer tissue in vivo, induce cytotoxic T cells (CTL) to the vascular endothelial cells of the tumor tissue, and induce the vascular endothelial cells of the tumor tissue
  • CTL cytotoxic T cells
  • the treatment can be performed under such conditions that the protein of the cancer cells is denatured while leaving the function as a cancer therapeutic drug, such as heat treatment, radiation treatment, or mitomycin C treatment.
  • a cancer therapeutic drug such as heat treatment, radiation treatment, or mitomycin C treatment.
  • the ratio of mitomycin C treatment method for example, dendritic cells were suspended at a density of 1 to 3 X 1 0 7 6 cells / mL, fine ⁇ 1 nil per mitomycin 'C 2 5 ⁇ 5 0 ⁇ g And incubate at 37 ° C for 30-60 minutes.
  • the heat treatment of cells for example, a centrifuge tube containing the cell suspension prepared live cell concentration to 1 X 1 0 7 or ZmL 5 0 ⁇ 6 5. It can be prepared by heating at 20C for 20 minutes.
  • the cancer targeted by the cancer therapeutic agent of the present invention is not particularly limited, but is preferably a solid cancer, for example, stomach cancer, liver cancer, colon cancer, lung cancer, skin cancer, bladder cancer, cervical cancer, ovarian cancer, breast cancer, Prostate cancer, brain tumor and the like.
  • the dosage of the dendritic cells of the present invention varies depending on the age, weight, sex, type of cancer, degree of progression of the cancer, symptoms, etc. of the patient, and cannot be determined unconditionally. It is only necessary to administer the same amount to the patient as to be injected with the liposome.
  • the dendritic cells of the present invention can be used for patients themselves, but due to the development of bone marrow banks and umbilical cord blood banks, they are administered to a large number of MHC-compatible patients of the same type. Examples that can be
  • cancer cell culture supernatant (cancer CM)
  • New medium Human umbilical cord vein endothelial cell culture medium; the following HUVEC medium.
  • CM action vascular endothelial cells were added with membrane vesicle preparation solution (dissolved 10 OmM paraformaldehyde, 2 mM dithiothreitol, ImM CaCl 2 , 0.5 mM MgCl 2 in DMEM medium) at 37 ° C , Processed overnight.
  • the supernatant is then centrifuged at 150 xg for 5 minutes, and then the supernatant is centrifuged at 4 ° C for 30 minutes. After centrifugation at 00 ⁇ g, the precipitate was used as a membrane vesicle of cancer CM vascular endothelial cells and used as an antigen to pulse to dendritic cells.
  • cell lysate obtained by suspending cultured vascular endothelial cells with CM acting on cultured cancer in physiological saline and repeating freeze-thaw four times was also used as an antigen to pulse dendritic cells.
  • Cancer CM Vessel endothelial cell membrane vesicles or cell lysate and lipofectin are mixed (in a quantitative ratio) and the lipid concentration is adjusted to 10%. And left at room temperature for 20 minutes. This was added to a cell suspension of mouse dendritic cell line DC2.4 cells or bone marrow-derived primary cultured dendritic cells (1 ⁇ 10 6 cells / mL), and incubated for 5 hours. After centrifugation and washing with a phosphate buffer, the cells were treated with mitomycin C (50 ⁇ g / mL) at 37 ° C for 30 minutes. The cells were centrifuged twice, washed and washed with a phosphate buffer, and resuspended in a phosphate buffer.
  • mitomycin C 50 ⁇ g / mL
  • B 16 F 10 cells (1 ⁇ 10 6 cells) were injected into the tail vein.
  • the number of lung metastases in the group receiving no dendritic cells was (924, 799, 550), and the number of lung metastases in the group receiving dendritic cells was (184, 414, 0). there were .
  • the dendritic cells of the present invention significantly suppressed lung metastasis of cancer cells, and were useful as cancer therapeutics.
  • Vascular endothelial cells subcultured from the aorta of the rat by the detachment method were used.
  • DMEM fetal serum
  • This vascular endothelial cell was used in the same manner as in Example 1 and a cell lysate was used as an antigen.
  • Example 2 Other operations were performed in the same manner as in Example 1 to culture vascular endothelial cells derived from aortic aorta in a medium containing the culture supernatant of B16 cells, and pulsed dendritic cells with the obtained cell lysate as an antigen. did.
  • the obtained dendritic cells were administered to B57 / BL6 mice in the same manner as in Example 1. Two weeks after the administration of the cancer cells, the lungs were removed and the lung weight was measured. As a result, as shown in Fig.

Abstract

L'invention concerne un remède contre le cancer. Ledit remède comprend, en tant que principe actif, des cellules dendritiques stimulées par un antigène issu de cellules endothéliales vasculaires cultivées dans un milieu contenant le surnageant de culture de cellules cancéreuses.
PCT/JP2003/014252 2003-02-17 2003-11-10 Remede contre le cancer WO2004071518A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002511623A CA2511623A1 (fr) 2003-02-17 2003-11-10 Remede contre le cancer
MXPA05008687A MXPA05008687A (es) 2003-02-17 2003-11-10 Remedio para cancer.
EP03815859A EP1595546A4 (fr) 2003-02-17 2003-11-10 Remede contre le cancer
JP2004568205A JPWO2004071518A1 (ja) 2003-02-17 2003-11-10 癌治療薬
US10/544,631 US20060062766A1 (en) 2003-02-17 2003-11-10 Remedy for cancer
AU2003277641A AU2003277641B2 (en) 2003-02-17 2003-11-10 Remedy for cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2003038117 2003-02-17
JP2003-038117 2003-02-17
JP2003039122 2003-02-18
JP2003-039122 2003-02-18

Publications (1)

Publication Number Publication Date
WO2004071518A1 true WO2004071518A1 (fr) 2004-08-26

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PCT/JP2003/014252 WO2004071518A1 (fr) 2003-02-17 2003-11-10 Remede contre le cancer

Country Status (8)

Country Link
US (1) US20060062766A1 (fr)
EP (1) EP1595546A4 (fr)
JP (1) JPWO2004071518A1 (fr)
KR (1) KR20050105454A (fr)
AU (1) AU2003277641B2 (fr)
CA (1) CA2511623A1 (fr)
MX (1) MXPA05008687A (fr)
WO (1) WO2004071518A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829113B2 (en) 2005-03-10 2010-11-09 Mebiopharm Co., Ltd. Liposome compositions
JP2013523824A (ja) * 2010-04-06 2013-06-17 ジョン ダブリュ． ホラデイ、 癌を治療する方法
JP2018070572A (ja) * 2016-10-24 2018-05-10 義之 小山 免疫治療システム

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US5962318A (en) * 1996-11-15 1999-10-05 St. Jude Children's Research Hospital Cytotoxic T lymphocyte-mediated immunotherapy
EP1639090A4 (fr) * 2003-06-09 2008-04-16 Univ Michigan Compositions et methodes de traitement et de diagnostic du cancer

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RAMAGE J. ET AL.: "DNA-Fc fusion vaccine targeting the end othelial antigen Tie-2", BRITISH JOURNAL OF CANCER, vol. 88, no. SUPPL.1, 2 July 2003 (2003-07-02) - 5 July 2003 (2003-07-05), pages S38, XP002904625 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829113B2 (en) 2005-03-10 2010-11-09 Mebiopharm Co., Ltd. Liposome compositions
US8758810B2 (en) 2005-03-10 2014-06-24 Mebiopharm Co., Ltd. Liposome compositions
JP2013523824A (ja) * 2010-04-06 2013-06-17 ジョン ダブリュ． ホラデイ、 癌を治療する方法
US9107878B2 (en) 2010-04-06 2015-08-18 Exocyte Therapeutics Pte, Ltd Methods of treating cancer
JP2017002054A (ja) * 2010-04-06 2017-01-05 エクソサイト セラピューティクス ピーティイー リミテッド 癌を治療する方法
JP2018070572A (ja) * 2016-10-24 2018-05-10 義之 小山 免疫治療システム

Also Published As

Publication number Publication date
EP1595546A4 (fr) 2010-08-04
US20060062766A1 (en) 2006-03-23
EP1595546A1 (fr) 2005-11-16
AU2003277641A1 (en) 2004-09-06
KR20050105454A (ko) 2005-11-04
MXPA05008687A (es) 2005-10-05
JPWO2004071518A1 (ja) 2006-06-01
AU2003277641B2 (en) 2009-09-17
CA2511623A1 (fr) 2004-08-26

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